The present invention relates to a use of a harpagid-related compound as an agent for treating arthritis, osteoporosis and ruptured disc, and to a pharmaceutical composition containing said harpagid-related compound as an effective component.
At present, it has been known that in Korea patients suffering from various bone diseases are on an increasing tendency annually. However, chemotherapy, operative therapy, etc. which have been currently used for the purpose of treating bone diseases have fail to realize the complete success as yet. Such bone diseases are advanced to chronic and degenerative state due to ageing, and further impose a great medical burden on a patient. Therefore, the development of novel materials which can be generally utilized in the clinical field is still urgently required.
It has been known that rheumatoid arthritis and degenerative arthritis known as typical adult diseases and geriatric diseases are an intractable disease (FIG. 2a), and are caused by a mechanism based on the activation of synovial cells in joint and the ageing due to such activation and the autoimmunological factors (FIG. 2b). It is expected that rheumatoid arthritis and degenerative arthritis can be cured by development of a drug which can kill or inhibit arthritic cells or inhibit or repress the expression of cyclooxygenase II (COX-II) as the enzyme produced by such arthritic cells (FIG. 2c).
The constituent drugs contained in the galenic composition developed by the resent inventors have been described in xe2x80x9cDongeubogamxe2x80x9d and xe2x80x9cSinnongbonchokyungxe2x80x9d as having various pharmacological activities including hematopoiesis, tonic, diuresis, bone marrow formation, recruitment of vitality and virility, effects on pre- and post-partum joint, lumbago, stomachic, anti-inflammatory, promotion of blood circulation and removal of blood stasis, elimination of nervous disorders, detoxication, hemostasis, effect of alleviating climacteric disorders, ernmenagogic effect, nutritive effect, hematic activity, etc. Further, other activities have also been disclosed in prior reference.
Throughout the whole world, the study of bone diseases has been actively conducted, and as a result, according to an increase of a series of immunological knowledge the etiology and mechanism of arthritic invasion have been revealed so that some agents for treatment of osteoporosis have been developed in recent days. Specifically, allendrate, tamoxifen, vitamin D3, parathyroid hormone (PTH) and COX-II inhibitor as an agent for treatment of rheumatoid arritis have already been successfully commercialized. Further, as an anti-inflammatory agent sulfasalazine (Becker K, Gromer S, Schirmer R H, Muller S., Thioredoxin reductase as a pathophysiological factor and drug target. Eur. J. Biochem., 2000 Oct., 15; 267(20):6118-6125) and thioredoxin reductase (a pathophysiological factor and drug target. Eur. J. Biochemn., 2000 Oct., 15; 267(20):6118-6125) have been known and are under either clinical trials or research and development. Meanwhile, as an agent for treatment of osteoporosis alendronate, raloxifene, calcitonin (Moraghan T J, Perez EA. Mayo Clin Proc. 2000 August; 75(8):821-9), estradiol (An-dersson T L, Stehle B, Davidsson B, Hoglund P. Maturitas. 2000 Jun. 30; 35(3):245-52), genistein (Mazurek A P, Polkowski K, Acta Pol Pharm. 2000 March-April; 57(2):135-55), 1,25-dihydroxyvitamin D3 (Am. J. Physiol. Endocrinol. Metab. 2000 July; 279(1):E213-20), patathyroid hormone (Hunziker 3, Wronski T J, Miller S C, J. Dent. Res. 2000 June; 79(6):1431-8), alendronate (Kashyap A S, Kashyap S. Postgrad Med J. 2000 July; 76(897):417-8), estrogen receptor modulators, calcitonin, and bisphosphonates (Wimal-Awansa S J. J. Clin. Densitom. 2000 Summer; 3(2):187-201) have been also disclosed.
Thus, in consideration of the problems caused in applying the prior drugs for the clinical purpose and involved in the toxic side effects, the present inventors have obtained the solvent fractions of Harpagophytum procumbens DC as one of medicinal plants and observed the inhibitory activity of respective fractions against proliferation of synovial cells in joint portion. As a result, we have demonstrated that ethyl acetate fraction (LNE fraction) and butanol fraction (LNB fraction) of Harpagophytum procumbens DC are effective.
Harpagophytum procumbens DC is a medicinal plant belonging to Pelaliacease, which inhabits the Kalahari Desert of Africa and is also called xe2x80x98Devil""s clawxe2x80x99 and of which rhizoma has been used for arthritis as a popular remedy in Africa and Europe [Schmidt, S.; Rothenfelde, B., The great significance of Harpagophytum root. Zeitschrift fxc3xcr Naturhcilkunde. 22, 48(1978); Seeger, P. C., Harpagophytum, an effective plant remedy, Effahrungsheilunde, vol. 8, 1978. Soulimani, R.; Younos, C.; Mortier, F.; Derrieu, C., The role of stomachal activity of plant extracts, using as an example extracts of Harpagophytum procumbens. Canad J. Physiol. Pharm. 72(12), 1532]. It has been known that Harpagophytum procumbens DC contains harpagide, harpahoside, procumbide [Kapf, R., Schweiz. Apoth.-Ztg., 114, 377(1976); Sticher, O., Dtsch. Apoth.-Ztg., 117. 1279(1977); Caprasse, M., J. Pharm. Belg., 35, 143(1980)], 8-O-(p-coumaroyl)-harpagide, 6-Oxe2x80x2-(p-coumaroyl)-procumbide and procumboside [Kikuch, Tohri; Matsuda, Satoko; Kubo, Yoko; Namba, Tsuneo, New iridoid glucosides from Harpagophytum procumbens DC. Chem. Pharm. Bull., 31(7), 2296(1983)]. However, no pharmacological activity has been known for the above components as yet.
The present inventors combined ethyl acetate fraction (LNE fraction) and butanol fraction (LNB fraction) as the effective fractions of Harpagophytum procumbens DC and then treated the mixture with silica gel chromatography to separate and purify LN-1, LN-2 and LN-3, respectively. As a result from determination of their chemical structures, it was identified that LN-1 is harpagoside, LN-2 is starchyose and LN-3 is harpagide. Harpagoside and harpagide are the compounds, which were already reported as being separated from Harpagophytum procumbens DC [von H. Lichti; A. von Wartburg, Die struktur des Harpagosides. Helvetica Chinica Acta, 49, Fasciculus 5, 1552(1996)], and starchyose is a kind of tetrasaccharides, which is contained in cotton seed and soybean in a relatively large quantity (Dong-Hoon, Kim, Food Chemistry, p185, 1978, Tamgudang), and was first isolated from Harpagophytum procumbens DC by the present inventors.
The present inventors have examined the effect on arthritis of the compounds isolated and purified from Harpagophytum procumbens DC. As a result, we have demonstrated that LN-3 (harpagide) is most effective and LN-1 (harpagoside) has a moderate pharmacological effect. Further, although it was already reported that harpagoside is heated under alkaline condition to produce harpagide [Kikuchi, Tohru; Matsuda, Satoko; Kubo Yoko; Namba, Tsuneo, New iridoid glucosides from Harpagophytum procumbens DC. Chem. Pharm. Bull., 31(7), 2296(1983)], the present inventors obtained the result that harpagide can be obtained from harpagoside even at room temperature without heating under alkaline condition.
However, the prior art did never disclose that harpagoside and harpagide have an anti-arthritic effect and an effect of treating osteoporosis and ruptured disc.
The present inventors have discovered the fact that the known compounds, harpagide and harpagoside, as the constituents of Harpagophytum procumbens DC exhibit a very potent anti-arthritic effect and also have an effect on osteoporosis, and thus, completed the present invention.
Therefore, the object of the present invention is to provide the pharmacological use of a harpagide-related compound represented by the following formula (I), in treating arthritis, osteoporosis and ruptured disc: 
in which
R1 represents hydrogen atom or alkyl group; and
R2 represents hydrogen atom or cinnamoyl group.
In the above formula (I), the compound wherein R1 is methyl and R2 is cinammoyl is harpagoside and the compound wherein R1 is methyl and R2 is hydrogen atom is harpagide.
Further, another object of the present invention is to provide a pharmaceutical composition containing the compound of formula (I) above as a major component.
Still another object of the present invention is to provide a process for converting harpagoside having a relatively weak pharmacological effect into harpagide having a relatively potent pharmacological effect.